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Does Cold-FX "Stop Colds"?

If you haven’t seen the Cold-FX commercial (6.5 MB video),[1] then you probably haven’t been watching TV recently, or at least not the Canadian channels. In the ad, a dishevelled male office worker standing by a photocopier sneezes a burst of saliva and mucus, presumably virus laden, towards a female co-worker walking confidently but unsuspectingly down the corridor. A voice-over says, “Boost your immune system, and help reduce the frequency, severity and duration of cold and flu symptoms with clinically proven Cold-FX, Canada’s number one selling cold remedy.”

The visuals promise much more, however. As the fog of infected sputum flies at her face, our ambush victim calmly extends her palm to halt the contagion. In the final scenes, a computer monitor displays a bottle of Cold-FX with the message “Clinically proven” followed by “Stop colds. Start now.”

That’s quite the promise. However, Cold-FX has undergone clinical trials, and on the strength of those trials, its manufacturer has been authorized by Health Canada to make a particular scientific-based health claim. It has also become a multi-million dollar seller. Could it be that Cold-FX has, in fact, been clinically proven to stop colds?

Preventing and Relieving Colds?

Answering this question first requires defining the word “stop”. It could be taken to mean cure, but as Jacqueline Shan, the former president of CV Technologies, has admitted, “There’s no cure for the common cold.”[2] So “stop” must mean prevent and relieve (i.e., symptomatically treat) colds short of actually curing them. In fact, the Cold-FX label has asserted in the past that the product could be used for “the prevention and relief of colds and flu”. As well, the company sells a three-day acute-dosing pack that it previously claimed was for “the immediate relief of colds and flu” – truly a hand in the path of viral spittle. Last March, the company was corrected by Health Canada for making these claims.[3][4]

CV Technologies have explained that this misunderstanding with Health Canada was just a procedural problem. They indicated that they were caught in the transition to the new natural health product (NHP) licensing process and requirements of the 2004 NHP Regulations and that they have since decided to pursue the licensing of only one health claim for Cold-FX at a time. Currently, they are focused on a low-dose, long-term cold prevention claim; in the future, they intend to submit a separate product license application for an acute-dose, short-term cold relief claim.[5]

Yet, these prevention and relief claims for Cold-FX do not seem to be backed up by published scientific data, at least not according to Health Canada. Instead, the regulators have judged that the evidence presented for the product’s license supports the more cautious health claim that was narrated in the commercial – “Helps reduce the frequency, severity and duration of cold and flu symptoms by boosting the immune system.”[6]

Boosting the Immune System?

But is that statement any better? Sadly, a health claim that includes the concept of “boosting the immune system” in general has little meaning in a medical context. As Quackcast‘s Dr. Mark Crislip points out, a claim for boosting the human immune system, with all its complexity, demands a more specific and detailed explanation. A general activating or priming of the immune system implies creating a generalized inflammatory response, which would likely lead to chronic health problems. In reality, normal people in good health can do little to improve on the baseline function of their immune system. Nonetheless, virtually every quack remedy and practice claims an ability to boost the immune system.[7]

In fairness, in vitro and in vivo trials[8][9] of Cold-FX’s active ingredient have reported some specific immunological effects, and blood samples taken during one of the clinical trials[10] have been reported to show some specific immunological differences, both increases and decreases, between the treatment and placebo groups.[11] Yet, it is not clear that these immunological findings have been consistent across all the clinical trials or that they are the mechanisms of action for the cold prevention and relief claims being made for the product. As Dr. Ronald Turner points out in commenting on the Predy trial:

The authors provide a summary of the immunological effects of North American ginseng, but it is not clear how these relate to viral respiratory infection. Enhancement of interferon-gamma activity might be expected to reduce the severity of symptoms, but enhancement of the elaboration of inflammatory cytokines might be expected to increase the severtity.[12]

In fact, CV Technologies have not published an explanatory model that demonstrates how the physiological processes related to these immunological findings explicitly account for the claims being made.

The Clinical Trials

Nevertheless, CV Technologies did submit a non-traditional (i.e., scientific) claim application[13] for Cold-FX’s product license, supported by clinical trial evidence, to the satisfaction of Health Canada. This is important to note because, in Canada, NHP manufacturers do not have to go to all that trouble to get their product licensed. Instead, they can just make a traditional claim application, for which they only have to show that the product has been used for a specified purpose in a culturally-based healing system for over 50 consecutive years.[14] That is, they don’t have to prove that their product works; they only have to prove that, for years, people have believed it works – no expensive, time-consuming, potentially disappointing clinical trials are required.

CV Technologies should be congratulated for doing the science. Skeptics often decry NHP manufacturers who hide behind traditional use claims or make product claims based solely on anecdotal evidence or pre-clinical observations. Instead, the company is attempting to prove their claims for Cold-FX scientifically through clinical trials, and proper ones at that – randomized, double-blind, placebo-controlled efficacy trials that were inspired by pre-clinical studies of the main ingredient American ginseng (panax quinquefolium).[15]

Perhaps the choice to make a
scientific claim was instigated by a true belief in the product’s efficacy by Jacqueline Shan, who was not only the former president of CV Technologies but also the chief scientific officer with PhDs in pharmacology and physiology,[16] or perhaps it was due to the lack of traditional evidence for any ginseng remedy related to the common cold.[17] In any case, proper clinical trials were conducted, and the results were accepted both by Health Canada and by at least two credible, peer-reviewed, medical journals. So it begs the questions – do these trials actually support the broad health claims being made by the company, especially by their marketing department, or do the trials even support the cautious claim that was approved by Health Canada?

This phase II trial was initially a single randomized, double-blind, placebo-controlled trial conducted during eight weeks of the 2000 cold and flu season with 89 healthy seniors (aged 60+ years old) in nursing and assisted-living homes. The purpose of the trial was to compare Cold-FX (200 mg given twice daily) against a placebo in preventing the incidence of acute respiratory illnesses (ARIs) as identified primarily through the self-reporting of symptoms[20] and secondarily through lab confirmation.[21] Because the ARI infection rate during this trial was insufficient to provide usable results, a second trial was conducted with 109 subjects during 12 weeks of the following year. In both trials, 90% of the participants had been vaccinated for influenza.

Trial Arm

Subjects

Symptom-definedARIs(primary endpoint)

Lab-confirmedFlu(secondary endpoint)

Lab-confirmedFlu or RSV(secondary endpoint)

Placebo

101

36 (35.6%)

7 (6.9%)

9 (8.9%)

Cold-FX

97

33 (34.0%)

1 (1.0%)

1 (1.0%)

Difference

—

NSS

6 (5.9%)

8 (7.9%)

Table 1 – Summary of Selected Trial Results for McElhaney (2004)

For both of the these individual trials, the differences between the Cold-FX and placebo groups for incidence, severity or duration of symptom-defined ARIs were found to be not statistically significant (NSS). When the results of the two trials were put together, still no significant differences were found for the primary endpoint – the incidence of symptom-defined ARIs. However, secondary analysis determined that fewer lab-confirmed flus and combined ARIs were experienced by the Cold-FX groups.

Although this trial was well designed, reviewers have criticized the interpretation of the results. For example, the study team described the combined reduction in lab-confirmed influenza and respiratory syncytial virus (RSV) as “an overall 89% relative risk reduction”[22] (i.e., an 8% reduction compared to a 9% incidence rate), which is true but misleading. In reality, there was simply an absolute risk reduction of 8% points.

Reviewers also expressed concern about combining the two trials. This methodology is often allowed, such as in multi-centric trials, but it is usually predetermined during the design of the trial so as to commit to the analytical procedure before trial data are collected. What is unclear here is – were these trials really two parts of the same trial, justifying combined analysis, or were they really different parts of a multi-centric trial, requiring meta-analysis? After a trial begins, altering the methodology risks allowing data-mining and committing such methodological errors as sharpshooter fallacy.

Because the two trials had procedural differences (e.g., trial length), because the overall ARI incidence rates were small and because the significant findings were secondary endpoints rather than primary ones, this combined trial is best interpreted as preliminary, but its secondary endpoint results justify a larger-scale trial to confirm the findings.

[Note: This trial has been included even though it is not clear that the journal in which it was published is considered a credible medical journal.]

This phase II trial was a randomized, double-blind, placebo-controlled trial conducted over a four month period in the early cold and flu season with 43 healthy seniors (aged 65+ years old) in nursing and assisted-living homes. The purpose of the trial was to compare Cold-FX (200 mg given twice daily) against a placebo in preventing ARI symptoms[25] as identified through self-reporting. At the four-week point, participants were vaccinated for three different influenza strains.

Trial Arm

Subjects

Incidence /Duration ofARI Symptoms(primary endpoint)

Incidence ofARI Symptomsin Last 2 Months(secondary endpoint)

Avg Duration ofARI Symptomsin Last 2 Months(secondary endpoint)

Placebo

21

NSS

13 (61.9%)

12.6 days

Cold-FX

22

NSS

7 (31.8%)

5.6 days

Difference

—

NSS

5 (30.1%)

7.0 days

Table 2 – Summary of Selected Trial Results for McElhaney (2006)

Overall, no significant differences were found between the Cold-FX and placebo groups for the primary endpoint – the incidence and duration of ARI symptoms. Secondary analysis determined that, in the Cold-FX group for the last two months of the trial, fewer people experienced ARI symptoms, and the average duration of symptoms was shorter.

Because of the small number of participants and the non-significant primary endpoint findings, this trial was definitely a preliminary trial, but its secondary endpoint results justify a larger-scale trial to confirm the findings.

This phase III trial was a randomized, double-blind, placebo-controlled trial conducted for four months during the 2003/2004 cold and flu season with 279 healthy subjects (aged 18-65 years old) who had contracted at least two colds in the previous year and who had not received a flu shot in the previous six months. The purpose of the trial was to compare Cold-FX (200 mg given twice daily) against a placebo in preventing the incidence of ARIs, which were identified through the self-reporting of symptoms and use of a modified Jackson criteria.

In the late 1950s, George Gee Jackson and colleagues conducted seminal research[28] on the common cold for which 1,000 subjects were infected with rhinovirus and instructed to self-report daily on eight cold symptoms – sneezing, headache, malaise, chilliness, nasal discharge, nasal obstruction, sore throat and cough – by scoring symptom severity as absent (0), mild (1), moderate (2) or severe (3). A six-day total symptom score greater than 13 (i.e., the Jackson criteria) was found to discriminate reliably between subjects with and without a lab-confirmed rhinovirus infection.

For this trial, the Jackson criteria was modified to use the more severe threshold of a two-day (instead of six-day) total symptom score greater than 14 (instead of 13). As well, a daily total symptom score greater than four was used as a threshold to assess the severity and duration of colds and symptoms.

This well-designed and rigorously-analyzed trial produced some marginally positive results. The number of cold sufferers in the Cold-FX and placebo groups were not significantly different, but there were fewer recurrent cold sufferers in the Cold-FX group. Overall, the Cold-FX group suffered fewer colds per person but only on the magnitude of 0.25 colds per person less. The Cold-FX group also experienced fewer symptoms and less cold duration, but the statistically analyzed differences were small, on the order of 1.3 to 1.6%.

One criticism made of this trial is the use of the modified Jackson criteria. The original Jackson criteria was based on induced rhinoviral infection and was validated using bacteriological cultures and blood tests. By not adhering to the criteria and not conducting lab confirmation, the study team for this trial did not validate their claims regarding “Jackson-verified colds”,[30] nor did they reliably distinguish colds from influenza or other types of ARIs. As well, because a more stringent threshold was used for the modified criteria, the trial discriminated acute “colds” but not necessarily all colds.

Another criticism is the continued tendency in these trials to verge on data-mining. Despite no significant results found for subjects who suffered at least one cold (a primary endpoint), secondary analysis found positive results for subjects who suffered two or more colds. However, the trial did not look into or report on whether this result held for three or more colds. Perhaps the positive result for two or more colds was a statistical anomaly. That is the problem with secondary endpoints; trial designs do not necessarily have procedural safeguards to refute or further validate them. The study team may have done so in this case but did not report on it.

At best, the results of this trial might support a claim that a person who takes two 200 mg Cold-FX capsules everyday for four months may have a 1-in-4 chance of not getting a second cold during that period and may knock a couple days and a few sniffles off the first cold. At a market price of $25 for 60 capsules, this preventative strategy would cost approximately $100 for the four months.

Science vs Marketing

Yet, even this modest claim is questionable. This series of trials has produced inconsistent results, and so it is hard to see how the trials, taken collectively, could definitively support any specific claim. McElhaney (2004) tells us that Cold-FX has no effect on symptom-defined ARIs but reduces lab-confirmed ones, while Predy (2005) does not report on lab-confirmed ARIs but discovers reductions in symptom-defined ones. McElhaney (2006) finds that Cold-FX has no effect on the incidence and duration of ARI symptoms over a four-month period, but Predy (2005) does observe reductions in symptoms over that period. Even in Predy (2005) on its own, there is seeming inconsistency. The product shows a preventative effect against recurrent colds but not against single incidents of them. In fact, if there is any consistency across the trials, it is the weakness and often failure to find support for the primary endpoints of the trials. It typically took secondary analysis to come up with significant findings.

That is not to say these trials were a waste of time. In as much as they can be considered preliminary, the trials can be used to refine the experimental conditions and expectations for follow-on phase III trials that may be able to confirm reliable results. Since some of the findings seem to be significant, they are worthy of follow-up. After all, it is entirely possible for American ginseng to have a pharmacoactive constituent that might prevent or relieve ARIs or at least reduce the symptoms. However, more substantial trials with consistent, reproducible results, along with an explanatory physiological model involving the active ingredient, should be required to support such claims.

CV Technologies would probably disagree with that assessment, likely asserting instead that they have established their efficacy claims. Nevertheless, they are pursuing the follow-on investigations that critics say are needed and that the scientific process requires. The following are some of the randomized, double-blind, placebo-controlled trials that the company is either conducting or has yet to report on yet:[31]

Acute Dosing (Phase II). The purpose of this four-day trial with 50 healthy adults is to compare the effect of the acute-dosing regimen of Cold-FX (600 mg three times daily on first day; 400 mg three times daily on second day; 200 mg three times daily on third day) against a placebo on several specified immunological responses assessed by blood tests. The completion of this trial was scheduled for July 2007.[32]

Hay Fever (Phase II). The purpose of this four-week trial with 200 hay fever suffers is to compare Cold-FX (400 mg daily) against a placebo in reducing the incidence, severity and duration of seasonal allergic rhinitis symptoms. The completion of this trial is scheduled for January 2010.[33]

Large-scale Follow-on with Lab Confirmation (Phase III). The purpose of this six-month trial with 780 community dwelling seniors is to compare standard-dosing Cold-FX (400 mg daily) and heavy-dosing Cold-FX (800 mg daily) against a placebo primarily in preventing lab-confirmed ARIs and secondarily in reducing the incidence, severity and duration of ARI symptoms and symptom-defined colds. The completion of this trial was scheduled for December 2008.[34]

Leukemia (Phase III). The purpose of this three-month trial with 336 chronic lymphocitic leukemia (CLL) patients is to compare Cold-FX (400 mg daily) against a placebo primarily in reducing the incidence of ARIs and secondarily to reducing the severity a
nd duration of ARIs and to the incidence of other specified types of infections related to CLL. The completion of this trial is estimated to be April 2009.[35]

Here again, CV Technologies should be congratulated. These trials address many of the deficiencies identified in the previous trials. The Acute Dosing trial begins to examine the relief claim in addition to the prevention claim. The Hay Fever trial may help to refine the types of ARIs that may be affected. The Large-scale Phase III trial should address the consistency and reproducibility problems with the existing trials, and the lab confirmation for the trial will give the results needed rigour. Finally, the Leukemia trial involves a variety of blood tests that should clarify if any relevant immunological affects are occurring. Certainly after these trials, CV Technologies will be much better positioned to know whether there are any specific health claims that can be supported or whether some or all of the results to date have been anomalous.

Yet, Cold-FX is not simply a promising test product that is working its way through a series of clinical trials; it is an existing commercial product that accounts for millions of dollars in revenue. Sales must be made, and cash flow must be maintained. There is significant pressure to market the product whether the science is mature or not.

All of the [Cold-FX] trials described [in the monograph] are manufacturer-sponsored. Although methodology and outcomes are in general portrayed according to accepted scientific standards, these reports do tend to highlight positive findings rather than limitations.[36]

Marketing spin has resulted. An 8% point reduction in incidence of respiratory infection is portrayed as a relative risk reduction of 89%,[37] an average reduction of 0.25 recurrent colds per person is described as a relative risk reduction of 56%,[38] and suggestive preliminary findings of prevention become an exhortation to “Stop Colds”. Yet, what happens if continued testing fails to support or substantially disproves the efficacy of the product?

Natural remedies don’t enjoy the same kind of patent protections as mainstream drugs, [Claude Camire, a pharmaceutical and biotech analyst] noted; as a result, they are too reliant on marketing. “If you tell me their clinical trials don’t back the product up, well, they’ll have very few analysts to take a gamble on perception.”[39]

Does Cold-FX “Stop Colds”?

Supporters of the research effort behind Cold-FX point out that its high quality, peer-reviewed trials are rare in the licensing of NHPs and that the rigour of the trials combined with the suggestive results provide far better evidence for efficacy than competing products, such as Airborne and Cold-Eeze. This praise almost implies that claims for the product should be accepted on the basis of effort to prove the claims rather than the proof itself, but even these advocates have qualified their support by saying that the trials are “not yet definitive”, “too early to conclude” and even “weak”.[40]

In the end, it is the evidence, and just the evidence, that counts. As much as CV Technologies believe Cold-FX is effective and as promising as they assert the results are so far, reviewers caution that the evidence is insufficient to date.

Experience has demonstrated the difficulty and importance of sound methodology in preventing bias in studies of common cold prevention. Although numerous therapies, both alternative and conventional, have been reported in preliminary studies to have beneficial effects for the common cold, only a relative handful have proven effective after rigorous and reproducible studies. Further studies that evaluate the effect of well-characterized and standardized preparation of ginseng in virologically proven influenza infections or more typical common cold illnesses will be needed to confirm and extend the results of [Predy (2005)].[41]

Indeed, anecdotal evidence and early studies on the abilities of echinacea and vitamin C to prevent and treat colds looked promising initially but failed to hold up under closer scutiny and continued testing.[42][43] Cold-FX may fit this same model as well, but only time will tell.

aside from the Predy trial, none of the studies cited [in the monograph] can be considered confirmatory Phase 3 trials. Even the Predy trial is limited in sample size and drop-out rate, as well as by lack of identification of specific viruses involved. Hence, while intriguing and promising, further development and corroboration may be required by some health organizations before the evidence of [Cold-FX] could be interpreted as sufficiently robust for incorporation into health policy and practice.[44]

The potential for a reversal in findings calls into question Health Canada’s licensing of the health claim for the product. Given the hesitance of the Cold-FX reviewers to endorse the product’s efficacy without reservation, it looks as if Health Canada may have acted prematurely in authorizing the claim. If further trials fail to support any effect for Cold-FX on colds and flu, will Health Canada have the resolve to revoke the authorization?

So, does Cold-FX stop colds? There is no published evidence to support such a definitive claim, nor according to reviewers, is there sufficient evidence at present to support definitively the related prevention and relief claims.[45] Yet, despite the company’s ambitious marketing, they have acted responsibly in conducting the current and upcoming clinic trials. While we wait for more evidence, one reviewer suggests an alternative cold prevention approach:

we await more data to quantify the efficacy and toxicity of [Cold-FX] … However, there is one intervention that, if performed correctly and frequently, can help reduce the incidence of outpatient visits for acute respiratory infections. [see Ryan (2001)] It has a great safety profile, is inexpensive and freely available (at least in North America): advise people to frequently wash their hands.[46]

^ The summary and assessment of this trial is based on the reviews by Drs. Barrett and Brown [Barrett (2007) 19-20], Drs. Nguyen and Slavik [Nguyen (2006)], and Drs. McCormack and Loewen [Baines (2006a,b)].

^ A symptom-based diagnosis of ARI was defined as identification of the new onset of a respiratory symptom (cough, sore throat, nasal congestion, sinus congestion or runny nose) along with another respiratory symptom or a constitutional symptom (feverishness, chills/sweat, myalgia, fatigue, headache, poor endurance or increased shortness of breath). [Barrett (2007) 20]

^ Lab confirmation was by viral throat or nasal culture for the presence of influenza, respiratory synctial virus (RSV), parainfluenza and rhinovirus [Barrett (2007) 20]. The report abstract also indicates that serology was also used to test for influenza. [McElhaney (2004)]

^ The summary and assessment of this trial is based on the reviews by Dr. Turner [Turner (2005)], Drs. Barrett and Brown [Barrett (2007) 19-20], Drs. Nguyen and Slavik [Nguyen (2007)], and Drs. McCormack and Loewen [Baines (2006a,b)].

^ “Statistical analyses were performed on the log-transformed data; differences and confidence intervals were obtained by transforming back to the original scale using antilogs.” [Predy (2005) 1046, Table 3].

Jackson, G.G. et al. (1958) “Transmission of the common cold to volunteers under controlled conditions. I. The common cold as a clinical entity.” American Medical Association Archives of Internal Medicine 101(2): 267-78, February.

Comments (5)

and who are YOU employed by, or lobby for, or which monied families blood runs thru your veins…?Just curious because you sure sound like you have an agenda. Hmmm IF Cold FX wasn’t a viable remedy then why oh why did a Pharmaceutical company just so happen to buy it today in a multi-million dollar deal?? What’s your wise and wordy answer for that oh sagely sceptic?

[quote name=cm]and who are YOU employed by, or lobby for, or which monied families blood runs thru your veins…?Just curious because you sure sound like you have an agenda. Hmmm IF Cold FX wasn’t a viable remedy then why oh why did a Pharmaceutical company just so happen to buy it today in a multi-million dollar deal?? What’s your wise and wordy answer for that oh sagely sceptic?[/quote]Hi CM. Based above, it doesn’t look like you read the extremely well researched article you are commenting on. Also, based on your tone, I doubt you want to engage in a discussion so much as throw stones. Despite that, I would suggest you take the time to actually read the article. In the meantime, allow me to pull out the conclusion for you:

“So, does Cold-FX stop colds? There is no published evidence to support such a definitive claim, nor according to reviewers, is there sufficient evidence at present to support definitively the related prevention and relief claims. Yet, despite the company’s ambitious marketing, they have acted responsibly in conducting the current and upcoming clinic trials. While we wait for more evidence…”

I, personally, fail to see how that indicates an agenda in any way. It simply states that the evidence is insufficient. As to the pending purchase of Cold FX, I would again quote the article:

“It has also become a multi-million dollar seller”

So, regardless of whether it works; people are buying it and the product is profitable. Seems like simple economics, no?

[quote name=cm]and who are YOU employed by, or lobby for, or which monied families blood runs thru your veins…?Just curious because you sure sound like you have an agenda. Hmmm IF Cold FX wasn’t a viable remedy then why oh why did a Pharmaceutical company just so happen to buy it today in a multi-million dollar deal?? What’s your wise and wordy answer for that oh sagely sceptic?[/quote] pharma companies only buy remedies so you can’t get them, big pharma has no interest in curing you. they just want you comming back.